Arylthiopyrrole (AThP) derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors: Synthesis, structure-activity relationships, and docking studies (Part 1)

Novel arylthio isopropyl pyridinylmethylpyrrolemethanol (AThP) derivatives 3-5, which ore related to capravirine (S-1153), were synthesized and tested for their ability to block the replication cycle of HIV-1 in infected cells. The newly synthesized AThPs are active in the concentration range of 0.008-53 mu m. Even if compounds 3-5 are generally less potent than S-1153, their SI values ore in some cases similar to that of the reference drug. In fact, the cytotoxicities of AThPs are generally lower than that of S1153. Compound 4e was the most active derivative of this series in cell-based assays; its potency is similar to that of S-1153 (EC50=8 and 3 nm, respectively), as is its selectivity index (SI= 6250 and 7000, respectively). AThP derivatives were proven to target HIV-1 RT In fact, compounds 3-5 generally inhibited the viral enzyme at concentrations similar to those observed in cell-based assays. A selected number of AThPs (4k and 5a,e) were tested against clinically relevant drug-resistant forms of recombinant reverse transcriptase (rRT) carrying the K103N and Y1811 mutations. Carbamate 5e showed an approximate 240-fold decrease in activity against Y1811, but only a 10-fold loss in potency against the K103N rRT form. Docking calculations were also performed to investigate the binding mode of compounds 2, 4e, 4j, 4k and 5e into the non-nucleoside binding site of HIV-1 RT and to rationalize some structure-activity relationships and resistance data.